Nephrogenic Systemic Fibrosis (NSF)

What is NSF? How does gadolinium cause it?

Nephrogenic systemic fibrosis (NSF) is a rare, progressive, usually fatal disease characterized by skin thickening, painful joint contractures, and fibrosis of multiple organs including the lungs, liver, muscles, and heart. Nearly all documented cases have occurred in patients with chronic severe renal insufficiency who have received gadolinium contrast. The association between gadolinium and NSF was first reported by Danish nephrologists in 2006. Between 2006 and 2010 several hundred cases were diagnosed worldwide.

NSF usually develops clinically within days to months following gadolinium exposure, although rare cases have been reported years later. Nearly all patients have been in severe renal failure, and many were on dialysis. To my knowledge only one case has occurred in a patient with a GFR slightly greater than 30 mL/min/1.73m². High and/or multiple doses of contrast are frequently reported, though the disease has occurred after a single dose (0.1 mmol/kg).

The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators.

The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Zn+2 or Ca+2) through a so-called transmetalation reaction :

(Metal ion) + Gd-Chelate ↔ Metal-Chelate + Gd+3

The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed engulfed by macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease.

Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been completely eliminated due to these measures.

The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.